Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mitoxantrone-resistant human MCF-7 breast cancer subline (MCF/MX) which is approximately 4000-fold resistant to mitoxantrone was isolated by serial passage of the parental wild-type MCF-7 cells (MCF/WT) in stepwise increasing concentrations of drug. MCF/MX cells were also approximately 10-fold cross-resistant to doxorubicin and etoposide but were not cross-resistant to vinblastine. Intracellular accumulation of radiolabeled mitoxantrone was markedly reduced in MCF/MX cells relative to that in the drug-sensitive MCF/WT cells. This decrease in intracellular drug accumulation into MCF/MX cells was associated with enhanced drug efflux, which was reversed when cells were incubated in the presence of sodium azide and 2, 4-dinitrophenol, suggesting an energy-dependent process. Incubation of MCF/MX cells with verapamil did not affect either the accumulation of mitoxantrone or the level of resistance in these cells. Furthermore, RNase protection and Western blot analyses failed to detect the expression of the mdr1 RNA or P-glycoprotein, a drug efflux pump known to be associated with the development of multidrug resistance in vitro. However, a polyclonal antibody directed against a synthetic peptide corresponding to the putative ATP binding domain of P-glycoprotein reacted with two (M(r) 42,000 and 85,000) membrane proteins from MCF/MX cells which were not found in MCF/WT. Functional assays and Western blot analysis for topoisomerase II revealed no differences in topoisomerase II activity or protein levels in MCF/MX cells. Thus, resistance in this cell line is apparently associated with enhanced drug efflux involving a pathway distinct from the mdr1-encoded multidrug transporter P-glycoprotein.
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PMID:Reduced intracellular drug accumulation in the absence of P-glycoprotein (mdr1) overexpression in mitoxantrone-resistant human MCF-7 breast cancer cells. 135 31

In an effort to improve the cytotoxicity of clinically used anticancer alkylating agents, the topoisomerase II inhibitory drugs U73-975 or mitoxantrone were added to cell cultures exposed to CDDP, carboplatin, BCNU, melphalan or thiotepa. In the MCF-7 human breast cancer cell line and in the MCF-7/CP (CDDP resistant) subline, U73-975 and mitoxantrone were both potent cytotoxic agents (IC50 0.002 microM and 0.006 microM for U73-975, respectively and 0.8 microM and 0.1 microM for mitoxantrone, respectively). As evaluated by isobologram analysis, the addition of either U73-975 or mitoxantrone to 1 h exposure to CDDP resulted in greater-than-additive killing in the MCF-7 parent cells. While U73-975 was also greater-than-additive in cytotoxicity with CDDP in the MCF-7/CP line, mitoxantrone and CDDP were only additive in cytotoxicity in these cells. In the case of carboplatin, the addition of U73-975 or mitoxantrone to treatment with the drug resulted in greater-than-additive cell killing in the MCF-7 parental cell line but in the MCF-7/CP cell line these combinations were only additive in cell killing. Addition of U73-975 to treatment with BCNU resulted in only additive cytotoxicity in both cell lines; however, the combination of mitoxantrone with BCNU resulted in greater-than-additive cell killing in both the parental and CDDP resistant cell lines. When either U73-975 or mitoxantrone was added to treatment with melphalan greater-than-additive cytotoxicity resulted in both cell lines except at low melphalan concentrations in the MCF-7/CP cell line. Finally, the addition of either modulator to treatment with thiotepa in the MCF-7 cell line produced variable interactions depending on thiotepa concentration, but in the MCF-7/CP cell line either modulator in combination with thiotepa caused greater-than-additive cell killing. These results indicate that the addition of topoisomerase II inhibitory drugs may substantially increase the cytotoxicity of some alkylating agents. In vivo experiments are necessary, however, to ascertain whether a therapeutic gain is achievable.
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PMID:Combination of the minor groove-binder U73-975 or the intercalator mitoxantrone with antitumor alkylating agents in MCF-7 or MCF-7/CP cells. 176 99

Etoposide (VP-16) resistance is expressed following in vitro exposure of HN-1 and MCF-7 human tumor cells to the drug itself or to fractionated X irradiation. VP-16-selected sublines prove cross-resistant to Adriamycin, amsacrine and actinomycin D, whilst X-ray-pretreated sublines show cross-resistance to only actinomycin D. These differential responses, in the HN-1 series, are not associated with significant differences in amounts of immunoreactive topoisomerase (topo) II, altered topo-II catalytic activity of nuclear extracts or changes in susceptibility of the topo II to VP-16- or amsacrine-induced DNA-protein cross-link formation. Therefore significant modifications in topo II appear not to be implicated in VP-16 resistance in these HN-1 sublines.
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PMID:A lack of detectable modification of topoisomerase II activity in a series of human tumor cell lines expressing only low levels of etoposide resistance. 184 24

The in vitro effects of the 2-(arylmethylamino)-1,3-propanediols (AMAPs) on macromolecular synthesis have been examined using the murine leukemia, P388, and the human mammary adenocarcinoma, MCF-7, under conditions of short-term drug exposure. AMAPs that were observed to inhibit macromolecular synthesis produced nearly equipotent inhibition of DNA and RNA synthesis. Equivalent inhibition of protein synthesis generally required significantly greater concentrations of AMAP. There is a general correlation between inhibition of polynucleotide synthesis and in vivo antitumor activity. The effects of four clinical candidate AMAPs (crisnatol, 773U82, 502U83, and 7U85) on macromolecular synthesis were further compared with those of actinomycin D, doxorubicin, mitoxantrone, etoposide, amsacrine, and cisplatin in MCF-7 cells. The pattern of AMAP action was most similar to that observed for doxorubicin and mitoxantrone. Finally, the effects of these four AMAPs on the size, specific activity, and rate of incorporation of [3H]-dTTP into DNA of MCF-7 cells synchronized by pretreatment with hydroxyurea was determined. It was found that DNA synthesis was inhibited by AMAPs independent of inhibition of the uptake, phosphorylation, or retention of the metabolic precursors. These results support the theory that antitumor AMAPs interfere with the normal functioning of enzymes, such as topoisomerase II or DNA and RNA polymerases, which interact with DNA.
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PMID:Effects of isomeric 2-(arylmethylamino)-1,3-propanediols (AMAPs) and clinically established agents on macromolecular synthesis in P388 and MCF-7 cells. 187 97

The cytotoxicity of etoposide and its analogues, dihydroxy (DHVP), o-quinone (VP-Q) and o-methyl (VP-OMe), was evaluated in human breast (MCF-7) and HL60 tumour cells. Although less potent than etoposide, both DHVP and VP-Q were cytotoxic to these cells. However, VP-OMe was inactive. Studies with purified topoisomerase II showed that the intensity of DNA cleavage and the pattern of cleavage were similar for DHVP, VP-Q and etoposide. In contrast, the VP-OMe failed to induce DNA cleavage, indicating that the presence of 4'-OH is essential for metabolism, induction of topoisomerase II-mediated DNA cleavage and cytotoxicity of etoposide and its analogues.
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PMID:Structure-activity relations, cytotoxicity and topoisomerase II dependent cleavage induced by pendulum ring analogues of etoposide. 216 77

Pleotropic resistant human breast cancer cells (MCF-7), selected for resistance to Adriamycin, were used to study the production of DNA strand breaks by etoposide (VP-16) and its relationship to drug cytotoxicity. It was shown that the resistant MCF-7 cell line was cross-resistant to VP-16, and the degree of resistance was found to be 125-200-fold. Alkaline elution studies indicated that the parental cell line was very sensitive to VP-16 which caused extensive DNA strand breakage. In contrast, little DNA strand breakage was detected in the resistant MCF-7 cells, even at very high drug concentrations, indicating a good agreement between strand breaks and cytotoxicity. Further studies indicated that the nuclei isolated from the parental cell line were more resistant to VP-16-induced DNA strand breaks than the intact cells, while the opposite was found in the resistant cell line. In addition, the alkaline elution studies in isolated nuclei showed only a 2-fold reduction of VP-16-induced DNA breaks in nuclei from the resistant cells. In agreement with this result, it was found that nuclear extract from the resistant cells produced 2-3-fold less VP-16-induced DNA breaks than that from the sensitive cells in 32P-end-labeled SV40 DNA. VP-16 uptake and efflux studies indicated that there was a 2-3-fold decrease in net cellular accumulation of VP-16 in the resistant cells. Although the reduced uptake of VP-16 and decreased drug sensitivity of topoisomerase II appear to contribute to the mechanism of action and the development of resistance to VP-16, they do not completely explain the degree of resistance to VP-16 in this multidrug-resistant MCF-7 cell line indicating that other biochemical factors, such as activation of VP-16, are also involved in drug resistance and suggesting that the resistance is multifactorial.
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PMID:DNA strand breaks produced by etoposide (VP-16,213) in sensitive and resistant human breast tumor cells: implications for the mechanism of action. 284 45

The effects of mitoxantrone, an antineoplastic DNA intercalator, on topoisomerase I and II were studied in two human breast cancer cell lines. A large increase of topoisomerase I activity was found when cells were exposed to various doses of mitoxantrone. Maximal effect was achieved with 20 and 40 ng/mL in T47D and MCF-7 cells respectively. The enhancement on topoisomerase I activity seemed to be reversible, to be dependent on time of exposure to the drug and to require cellular integrity. Type II topoisomerase was inhibited in T47D cells after treatment for one hour with 10 ng/mL of mitoxantrone and enzyme activity was undetectable at higher doses (40 ng/mL). This inhibitory effect did not take place in vitro unless the concentration of the intercalator was increased to 400-500 ng/mL.
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PMID:Mitoxantrone affects topoisomerase activities in human breast cancer cells. 301 Sep 82

In previous studies we have reported that preactivated merocyanine 540 (pMC540) and its chemically synthesized isolates merocil and merodantoin mediate their preferential cytotoxicity towards certain types of malignant cells including human breast cancer cells in vitro and in vivo. The mechanism of cytotoxic action appears to be, in part, via initial interaction with topoisomerase II leading to apoptosis. To further build upon these findings we now show that pMC540 and merodantoin disrupt mitochondrial morphology and function in intact MCF-7 human breast cancer cells as seen by their causing the release of rhodamine 123 from prestained cells, a rapid reduction in ATP levels, inhibition of succinate dehydrogenase activity and oxygen consumption. These data suggest that mitochondria may also be an important target for the cytotoxic action of pMC540 and merodantoin mediated through disruption of the energy balance.
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PMID:Relationship of mitochondrial function and cellular adenosine triphosphate levels to pMC540 and merodantoin cytotoxicity in MCF-7 human breast cancer cells. 757 58

In the MCF-7 human breast tumor cell line, the topoisomerase II inhibitor, VM-26, produces a concentration dependent reduction in expression of the oncogene c-myc which parallels growth inhibition. Down-regulation of c-myc expression was examined at transcriptional and post-transcriptional levels. VM-26, at 10 microM, produced a reduction in the transcription rate of both sense and antisense strands of c-myc as determined by nuclear run-off analysis. In contrast, in the presence of the RNA synthesis inhibitor, actinomycin D, VM-26 failed to alter the half-life of the c-myc message. The capacity of VM-26 to reduce c-myc expression was not abrogated in cells pretreated with the protein synthesis inhibitor, cycloheximide (despite superinduction of c-myc expression in both control and VM-26 treated cells); this observation suggests that de novo protein synthesis may not be required to mediate the effects of VM-26 on steady state c-myc transcript levels. An extended analysis of the time course of c-myc expression demonstrated that the decline of steady state c-myc mRNA levels induced by VM-26 was biphasic, 6 h after the initial reduction in c-myc expression to approx. 30% of control levels, c-myc levels rebounded to 70% of control; after 24 h, c-myc expression declined gradually and remained at depressed levels (40% of control) at 48 and 72 h. These observations suggest that the initial transient reduction in c-myc expression associated with inhibition of transcription may represent a component of an early signalling pathway leading to growth arrest in MCF-7 breast tumor cells exposed to VM-26.
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PMID:Transcriptional down-regulation of c-myc expression in the MCF-7 breast tumor cell line by the topoisomerase II inhibitor, VM-26. 759 88

Suramin, a hexasulphonated naphthylurea with activity in prostatic cancer, possesses a wide variety of antitumour mechanisms of action, one of which is the inhibition of topoisomerase II. In this in vitro study, suramin was combined with the topoisomerase I inhibitor, camptothecin. Several suramin concentrations (0.2-3000 microM) were combined with camptothecin (0.4 pM-20 microM) in MCF-7 and PC3 human cancer cell line cultures. In addition, we studied the topoisomerase II and I gene expression by northern blot analysis, and the cell cycle distribution by flow cytometry, after exposure to suramin. While there was only an additive effect when suramin and camptothecin were added simultaneously, a remarkable synergism was obtained when camptothecin was added after a 3-day exposure to suramin. Topoisomerase II and I gene expression and the number of cells in S phase were significantly reduced after exposure to suramin. In conclusion, interaction of suramin with camptothecin is schedule-dependent and can be synergistic. These findings might help in identifying optimal combinations of suramin or other topoisomerase II inhibitors, with topoisomerase I inhibitors.
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PMID:In vitro sequence-dependent synergistic effect of suramin and camptothecin. 783 42


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